What is the best initial workup for a patient with elevated hemoglobin (Hb) levels?

Initial Workup for Elevated Hemoglobin

The best beginning workup for elevated hemoglobin should include a complete blood count with differential, comprehensive metabolic panel, erythropoietin level, arterial blood gas analysis, and JAK2 V617F mutation testing to differentiate between primary and secondary causes of erythrocytosis.

Understanding Elevated Hemoglobin

Elevated hemoglobin (Hb) levels, also known as erythrocytosis or polycythemia, are defined as:

• Hb >17 g/dL in men
• Hb >15 g/dL in women

Initial Diagnostic Algorithm

Step 1: Confirm True Erythrocytosis

• Complete blood count (CBC) with differential
• Repeat Hb measurement to rule out spurious elevation due to dehydration or stress 1
• Ensure proper hydration status before repeat testing

Step 2: Basic Laboratory Evaluation

• Comprehensive metabolic panel (including renal and liver function tests)
• Serum erythropoietin level
  • Low: Suggests primary polycythemia (e.g., polycythemia vera)
  • Normal/elevated: Suggests secondary causes

Step 3: Evaluate for Hypoxic Causes

• Arterial blood gas analysis to assess oxygen saturation
• Pulse oximetry (both at rest and with exertion)
• Consider sleep study if sleep apnea is suspected

Step 4: Molecular Testing

• JAK2 V617F mutation testing (primary screening test for polycythemia vera)
• Consider additional molecular testing (CALR, MPL) if JAK2 is negative but clinical suspicion remains high

Differentiating Primary vs. Secondary Causes

Primary Causes (Absolute Erythrocytosis)

• Polycythemia vera (PV)
  • JAK2 V617F mutation positive in ~95% of cases
  • Low erythropoietin levels
  • Often accompanied by leukocytosis and thrombocytosis

Secondary Causes (Relative or Absolute Erythrocytosis)

• Hypoxia-driven:
  • Chronic lung disease
  • Sleep apnea
  • High altitude residence
  • Smoking
  • Congenital heart disease
• Pathologic erythropoietin production:
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Renal cysts/hydronephrosis
  • Cerebellar hemangioblastoma
• Other causes:
  • Dehydration (relative erythrocytosis)
  • Androgen use
  • Certain medications

Common Pitfalls to Avoid

1. Failure to repeat testing: A single elevated Hb measurement may be spurious due to dehydration or stress 1

2. Overlooking smoking history: Active smoking can cause significant elevation in Hb levels through carbon monoxide-induced tissue hypoxia

3. Missing secondary causes: Not all elevated Hb is polycythemia vera; thorough evaluation for secondary causes is essential

4. Inadequate molecular testing: JAK2 V617F testing should be performed in all patients with unexplained erythrocytosis, as it's positive in most cases of polycythemia vera

5. Not considering relative erythrocytosis: Plasma volume contraction (dehydration) can cause apparent elevation in Hb without true increase in red cell mass

Special Considerations

• In patients with chronic kidney disease, evaluate for inappropriate erythropoietin production or use of erythropoiesis-stimulating agents 2

• For patients with elevated Hb approaching 12 g/dL on erythropoiesis-stimulating agent therapy, dose reduction is indicated 3

• Consider family history of erythrocytosis which may suggest rare congenital causes 2

By following this systematic approach, the underlying cause of elevated hemoglobin can be identified efficiently, allowing for appropriate management to reduce morbidity and mortality associated with erythrocytosis, particularly the risk of thrombotic events.